A dual-responsive CO-releasing nanogel ameliorates retinal ischemia–reperfusion injury by restoring mitochondrial homeostasis and attenuating cGAS-STING pathway activation

Retinal ischemia–reperfusion injury (RIRI) represents a central pathological mechanism underlying neurodegeneration in multiple blinding ocular diseases, including glaucoma, diabetic retinopathy, and retinal vein occlusion. Ischemic stress triggers a surge of reactive oxygen species (ROS) within retinal ganglion cells, leading to mitochondrial dysfunction and initiating a vicious cycle of cellular damage. Targeting the regulation of redox balance within the RIRI microenvironment to restore mitochondrial homeostasis remains a major challenge in RIRI therapy. Here, a dual ROS-responsive carbon monoxide (CO) prodrug nanoplatform (COPN) was developed. This system integrates a ROS-sensitive CO-releasing molecule, CORM401, as the active prodrug unit, which is encapsulated within a disulfide-crosslinked dendritic nanogel matrix, thereby enabling site-specific CO release under pathological oxidative conditions. Locally released CO effectively neutralizes excessive ROS, restores mitochondrial quality control, and prevents mitochondrial DNA cytosolic leakage, thereby attenuating cGAS–STING pathway activation and subsequent neuroinflammatory responses. Furthermore, COPN successfully reverses ischemia-induced immunometabolic dysregulation, restores oxidative phosphorylation capacity, and enhances cellular metabolic resilience. This study offers a promising therapeutic strategy with strong translational potential for treating oxidative retinal diseases.